Dysfunctional mammalian telomeres join with DNA double-strand breaks

Susan M. Bailey, Michael Cornforth, Robert L. Ullrich, Edwin H. Goodwin

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

In addition to joining broken DNA strands, several non-homologous end-joining (NHEJ) proteins have a second seemingly antithetical role in constructing functional telomeres, the nucleoprotein structures at the termini of linear eukaryotic chromosomes that prevent joining between natural chromosome ends. Although NHEJ deficiency impairs double-strand break (DSB) repair, it also promotes inappropriate chromosomal end fusions that are observed microscopically as dicentric chromosomes with telomeric DNA sequence at points of joining. Here, we test the proposition that unprotected telomeres can fuse not only to other dysfunctional telomeres, but also to ends created by DSBs. Severe combined immunodeficiency (scid) is caused by a mutation in the catalytic subunit of DNA-dependent protein kinase (DNA-PK), an enzyme required for both efficient DSB repair and telomeric end-capping. Cells derived from wild-type, Trp53-/-, scid, and Trp53-/-/scid mice were exposed to gamma radiation to induce DSBs, and chromosomal aberrations were analyzed using a novel cytogenetic technique that can detect joining of a telomere to a DSB end. Telomere-DSB fusions were observed in both cell lines having the scid mutation, but not in wild-type nor Trp53-/- cells. Over a range of 25-340cGy, half of the visible exchange-type chromosomal aberrations in Trp53-/-/scid cells involved telomere-DSB fusions. Our results demonstrate that unprotected telomeres are not only sensed as, but also acted upon, by the DNA repair machinery as if they were DSB ends. By opening a new pathway for misrepair, telomere-DSB fusion decreases the overall fidelity of DSB repair. The high frequency of these events in scid cells indicates telomere dysfunction makes a strong, and previously unsuspected, contribution to the characteristic radiation sensitivity associated with DNA-PK deficiency.

Original languageEnglish (US)
Pages (from-to)349-357
Number of pages9
JournalDNA Repair
Volume3
Issue number4
DOIs
StatePublished - Apr 1 2004

Fingerprint

Double-Stranded DNA Breaks
Telomere
Joining
Severe Combined Immunodeficiency
DNA
Repair
Fusion reactions
Chromosomes
DNA-Activated Protein Kinase
Aberrations
Chromosome Aberrations
Nucleoproteins
DNA sequences
Electric fuses
Gamma rays
Catalytic DNA
Machinery
Protein Deficiency
Mutation
Cytogenetic Analysis

Keywords

  • ALT
  • Alternative lengthening of telomeres
  • CO-FISH
  • DNA-dependent protein kinase
  • DNA-dependent protein kinase catalytic subunit
  • DNA-PK
  • DNA-PKcs
  • Double-strand break
  • DSB
  • FISH
  • Fluorescence in situ hybridization
  • Telomere repeat binding factor 2
  • TRF2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Dysfunctional mammalian telomeres join with DNA double-strand breaks. / Bailey, Susan M.; Cornforth, Michael; Ullrich, Robert L.; Goodwin, Edwin H.

In: DNA Repair, Vol. 3, No. 4, 01.04.2004, p. 349-357.

Research output: Contribution to journalArticle

Bailey, Susan M. ; Cornforth, Michael ; Ullrich, Robert L. ; Goodwin, Edwin H. / Dysfunctional mammalian telomeres join with DNA double-strand breaks. In: DNA Repair. 2004 ; Vol. 3, No. 4. pp. 349-357.
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